The major objectives of this project are to develop the Tg.AC transgenic mouse line as a model for (1) studying the multistage process of skin carcinogenesis; and (2) as a short-term (20-26 week) in vivo model for identifying chemicals that are promoters or complete carcinogens. The chemical activity data generated in the Tg.AC model has been recently accepted for determining human risk assessment as an alternative short- term test in place of the mouse component in the two-year bioassay. In the meantime our laboratory continues to conduct studies that may expand the use of the model for chemical testing; e.g., studies that involve routes of chemical administration other than the skin. The concordance of chemical activity between the NTP two-year bioassay results and that for the same chemicals in the Tg.AC mouse model is very high, over 80%. Other studies focus on the role of mitogenic factors in the induction of tumors during would repair. Progress has also been made in identifying the growth regulatory factors (endogenous mitogens) that activate the transgene. This is significant, because induction of the v-Ha-ras transgene has been found to accompany all spontaneous and induced tumors. Cross-mating Tg.AC mice with transgenic Cox-1, Cox-2, and TGF-alpha null mice provides offspring that permit the study of the role of inflammation and mitogenic cytokines in the induction of tumors. These studies are relevant to human health because ras family mutations are found in 40% of different human target organ tumor sites.